Award details

E-cadherin subcomplexes: function and regulation by microtubules

Reference	BB/K00056X/1
Principal Investigator / Supervisor	Professor Nicholas Brown
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Gurdon Institute
Funding type	Research
Value (£)	567,487
Status	Completed
Type	Research Grant
Start date	01/10/2012
End date	30/03/2016
Duration	42 months

Abstract

Cell adhesion is vital for attachment between adjacent cells and cell-cell communication. E-cadherin is one of the major transmembrane proteins to provide cell-cell adhesion in epithelial cells. Positioning of E-cadherin along the cell's apical-basal axis is important for adhesion, and it has recently become clear that the distribution of E-cadherin around the periphery of the cell, within the zonula adherens, is also tightly controlled. It is an active process to distribute E-cadherin evenly around the periphery, and there are increasing numbers of cases where an asymmetric distribution is generated in the plane of the cell layer. This proposal describes research aimed at discovering the mechanisms that generate planar asymmetry in E-cadherin and its function in development and disease. This proposal follows on from our discovery that dynamic polarized microtubules generate the asymmetrical distribution of a newly defined sub-population of E-cadherin at cell-cell junctions in epidermal cells of Drosophila embryos. This E-cadherin pool is more dynamic (mobile) in comparison to the rest of E-cadherin (as defined by its rate of exchange), and is uniquely associated with the scaffolding protein Bazooka/Par-3 (Baz). The goals of this research are to identify the function of this asymmetrically distributed mobile E-cadherin and how microtubules ensure its junctional asymmetry. By manipulating Baz, we can downregulate mobile E-cadherin to test its function in diverse E-cadherin-dependent processes. We will identify other proteins that are part of the complex of mobile E-cadherin and Baz. We will focus on interacting proteins with enzymatic activity, e.g. kinases, and will elucidate how they contribute to mobile E-cad function. In parallel, we will study how microtubules ensure the asymmetry of Baz-bound E-cadherin. We will study how microtubules become polarized, and which molecular mechanism links them with Baz-bound E-cadherin to produce E-cadherin asymmetry.

Summary

The mechanism that attaches neighbouring units, or cells, in our body to each other is known as cell-cell adhesion. Recent work has demonstrated that cell-cell adhesion is also important for communication between the neighbouring cells to decide when to divide, migrate or die. Specific cell adhesion proteins ensure cell-cell adhesion: the proteins on the surface of one cell bind directly to similar proteins on the surface of adjacent cell. One of the major cell adhesion proteins is called E-cadherin. E-cadherin provides cell-cell adhesion between the epithelial cells: the cells that outline all cavities and surface structures of the body. In the cell, E-cadherin adhesion forms a thin belt, called zonula adherens that outlines the periphery of the cell and connects it to multiple neighbours. E-cadherin is vital for proper development of the body from very early stages. Furthermore, faulty E-cadherin adhesion contributes to cancer progression by increasing growth and metastasis. For proper cell-cell adhesion it is vital to position the zonula adherens at a particular distance from the surface of the cell that faces the cavity. More unexpectedly, the cell also carefully controls how E-cadherin is distributed around the circumference of the cell, within the zonula adherens. While most cells have an even distribution, an increasing number of cases have been discovered where E-cadherin is distributed asymmetrically. The function of such asymmetric distribution in the developing animal has yet to be tested. We have chosen a simple animal to study this problem, the fruit fly Drosophila. Fruit flies use E-cadherin in the same way as we do. For example, if fruit fly embryos lack E-cadherin they die early in development because epithelial cells cannot maintain contacts to each other and tissues fall apart. Our recent findings demonstrate that there are two different populations of E-cadherin in epithelial cells in Drosophila embryo. One population is distributed uniformly around cell periphery. Another population is distributed asymmetrically. This second population of E-cadherin is specifically associated with protein called Bazooka/Par-3, and its asymmetry requires a subtype of cytoskeleton: long tubular structures called microtubules. These findings raise several questions that are the focus of this proposal. First, do different E-cadherin populations have different functions? If they do then it may be possible to interfere with one without affecting the others, which could help control aberrant E-cadherin functions. Second, can we identify other proteins that work with the different E-cadherin populations to help us to understand what they do. We anticipate that proteins that are present in just one or other population may be used to regulate the levels, distribution or action of a particular E-cad population, and thus be targets for drug discovery, and in addition may prove to be mark out aberrant cells for diagnostic purposes. Third, we wish to discover how microtubules control E-cadherin asymmetry. Knowing this mechanism will allow us to manipulate E-cadherin asymmetry in the cells and specifically control this population. We anticipate that we will discover basic mechanisms that are shared between all animals. In future, we will be able to apply this knowledge to treatment of medical conditions arising from defects in E-cadherin function such as epithelia-derived tumours. For example, if we find that only one population of E-cadherin prevents excessive cancer growth, and we identify the molecules that specifically bind this population of E-cadherin, it will be possible to search for drugs that attack this population of E-cadherin to reduce cancer growth, without disrupting E-cadherin adhesion in the surrounding non-tumour cells.

Impact Summary

Beneficiaries: -Future patients suffering from cancer, especially carcinomas -Pharmaceutical and Biotech industries -Medical diagnosis of cancers -Those recruiting scientifically trained staff, including, business, industrial and public sector -The general public, who we hope will be inspired by our images, movies and discoveries Potential for cancer treatment: As E-cadherin is expressed in epithelia our studies are most relevant to carcinomas, which derive from epithelial cells. Carcinomas include breast, prostate, lung and colorectal cancers: the four most common cancers in UK (54% of all cancers; 165,876 diagnoses in 2008 and 73,803 deaths). Loss of or faulty E-cadherin is closely correlated with carcinoma progression, e.g. in breast cancer 90% of invasive lobular carcinomas had lost E-cadherin, and reciprocally, some aggressive breast cancers have elevated E-cadherin. This research could benefit patients in two ways: 1) by providing biomarkers that specifically label different E-cadherin populations with specific functions, thus permitting earlier diagnoses, e.g. if a specific E-cadherin complex inhibits cell proliferation, levels of proteins in this complex will reveal loss of anti-proliferative activity, before changes in overall E-cadherin levels can be detected. Early diagnosis is crucial for patient survival and well being, as it allows early treatment. Timescale 5 years. 2) by providing drug targets through the discovery of proteins specific to individual populations of E-cadherin. These proteins could be used to regulate the levels, distribution or function of a particular E-cadherin population. For example, if a population of E-cadherin promotes collective cell migration, inhibiting the proteins associated with it may inhibit breast cancer metastasis without destroying E-cadherin adhesion. Timescale for identification of targets and initial screening: 5 years. As carcinomas are predominantly diagnosed in older adults with, for example, 81% of breast cancers occurring in women aged 50 years or over, better diagnostics and treatment could contribute to healthy aging of affected individuals and allow sufferers to live longer and remain active longer contributing to society as a whole. Overall, the quality of life of the sufferers and their families could increase contributing to nation's health. Timescale 5-10 years. Biotech and Pharmaceutical Industries licensed to use and develop the above biomarkers and drug targets will benefit from their successful identification. Development of such products will be beneficial for the UK economy and attract investment from global business. Timescale 5 years. Medical services would benefit as consumers of these new products and services increasing efficiency in diagnosis and treatment of E-cadherin-associated diseases. Furthermore, medical services could benefit from better understanding of functions of E-cadherin in adhesion and signalling in healthy and diseased cells, as this would highlight new ways to prevent, diagnose and treat associated diseases. Timescale 5 years. Staff training: Not only will the two postdoctoral fellows supported by this grant improve their training but they will supervise A-level students doing work experience, and undergraduate projects, contributing to their rigorous training in scientific experimentation, good experimental design, and data analysis. Thus, this grant will contribute towards health of UK science and higher education through developing expertise in these scientific areas and training highly skilled researchers. Timescale 3 years. Inspiration of the general public: Through our engagement with the public through talks, websites, and general audience publications we seek to communicate the excitement and beauty of scientific research. Examining molecular and cellular behaviour in living developing animals provides beautiful images and movies that effectively capture and communicate the concepts of biomedicine.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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